Alcoholism is a significant public health problem because of its prevalence and the high morbidity to patients and high impact on their relatives. The alcohol dehydrogenase (ADH) cluster of genes and the aldehydedehydrogenase 2 locus. (ALDH2) are known to affect alcohol metabolism and the genetic susceptibility to alcoholism in some populations, primarily populations of East Asian ancestry. Our new haplotype analyses of the ADH gene cluster show significant linkage disequilibrium and attribute the effect on alcoholism in the Chinese sample analyzed to only one haplotype. Recent work by others similarly finds a single relevant haplotype at the ALDH2 locus. Other data suggest that alleles not yet identified at these loci may be relevant to alcoholism and/or alcohol metabolism in Asian and other populations. Considered with the realization of the complexity of global human genetic diversity (developed in part from previous work on this grant), these data support undertaking a comprehensive global survey of genetic variation at the ADH gene cluster and at the ALDH2 locus. Therefore we propose to extend the study of the haplotypes across these entire regions, by identifying polymorphisms encompassing the entire region with each gene covered at molecularly short distances and type the most informative markers on at least 38 in-lab population samples representing all major parts of the world. A combination of known and new makers encompassing ALDH2 will similarly be studied. Collaborators in China, India, and Africa will continue to help develop better coverage of populations in their regions for ADH and ALDH2 haplotypes. Studies of other higher primates (chimpanzees, gorillas, orangutans) to determine the direction of mutation for each human polymorphism will illuminate the evolutionary origins of the existing variation. We will continue to collaborate with other researchers to examine these haplotypes in three different sets of individuals with alcoholism, one Chinese, one German, and one Australian (Northern European ancestry) and communicate our polymorphism and haplotype data to collaborators working on the COGA and NIAAA linkage studies of alcoholism. Thus, this complex and multifaceted project will provide the necessary population genetic basis for further studies of the ADH and ALDH2 loci as related to alcoholism and will undertake different applications to alcoholism and alcohol metabolism using haplotype approaches. Indications of the importance to alcoholism of different genetic variants and of which haplotypes may harbor cryptic but functionally relevant variation will result from these studies.